Novel approaches in prognosis and personalized treatment of cancer

Abstract

The routine use of‘personalized cancer medicinein clinical settings has become justifiable for three reasons:(a)Rapid development of targeted therapies directed to various tumor types.(b)Therapeutic efficacy,benefiting from molecular and biological understanding of specific tumor types.(c)Improved proteomic and genomic biomarkers stratifying patients to particular strategies.The major ambition of current clinical research is to increase and optimize‘personalized cancer medicine’.This thesis demonstrates progress on‘personalized cancer medicine’based on four conclusions:(i)Two novel tissue biomarkers,FIH and E2F1,demonstrated independent prognostication for overall survival(OS) of renal cell cancer(RCC) patients,potentially influencing tumor staging and consequent clinical management.(ii)The Memorial Sloan Kettering Cancer Center(MSKCC) risk model is widely usedto allocate patients withmetastatic renal cell cancer(mRCC)into three prognostic risk groups(favourable,intermediate or poor) and correspondingly to differentlytargeted therapies.With a proteomics-based approach a novel biomarker Serum Amyloid Alpha(SAA) was identified in blood of mRCC patients.SAA demonstrated to be a robust and independent predictor for progression-free survival and OS in mRCC patients with equal prognostic accuracy,compared to the MSKCC risk model in two independent patient cohorts.When incorporated in the MSKCC model SAA improved the predictive accuracy of this model and thereforepatients risk categorization.Consequently,SAA -either alone or as part of the MSKCC model-may be used as an objective prognosticbiomarkerformRCC patients and improve the a-priori selection of appropriate risk-directed therapy for every individual,therebycontributingto more tailor-made therapeuticapproaches in clinical practice.(iii)Circulating mitochondrialDNA in plasma of cancer patients quantified by a newly developed and straightforward quantitativePCRshowed prognostic accuracyforOS in several cancer typesand might have significant importance as pan-tumorbiomarker.(iv)The authority of single-gene analysis,confined,as the mutational status throughout the entire pathway,might be responsible for therapy outcome.Another important limitation is that the genetic constitution of the metastasis is unknown.Therefore response to therapy is unpredictable.By employing the novel technology ‘Next Generation Sequencing’ this study comprehensively compared the genetic constitution of a composed ‘Cancer mini-Genome’ in 21 patients with primary CRC and their subsequent hepatic metastases.A ‘Cancer Mini-Genome’ was invented consisting of exons of 1,264 genes, including all relevant oncogenic and therapeutic pathways.Novel and known variations in the up/downstream genes ofEGFR/PI3K/VEGF/mTOR/TGFbeta-pathways were elucidated. On average 83(SD69) potentially function-impairing variations were gained in the metastasis and 70(SD48) variations were lost,showing that the genetic constitution of primary tumor and its subsequent hepatic metastasis are significantly dissimilar.These differencesare of such magnitude that an impact on treatment outcome is realistic andimplicates that for genetic pathway-analysis and subsequent adjustment of targeted therapy a biopsy of the metastasis is preferred to archived primary tumor tissue.This requires a different mindset for oncologists,because biopsies from metastases are not commonly taken at the start of treatment.Conclusively,genetic pathway-analysis of metastases might refine the selection of patients for targeted therapies,justifying additional modifications and optimization of currently treatment algorithms